Although protective armor and acute medical intervention allow soldiers to survive explosions, a growing number of veterans will have disability stemming from blast-related brain damage. Soldiers also return from combat with psychological disabilities caused by traumatic war events. The clinical presentations of individuals with blast-related brain damage and post-traumatic psychopathology markedly overlap and thus a clear description of the direct consequences of explosive blast is complicated by the emotional and cognitive sequelae of psychological trauma. The inability to clearly demonstrate the basis of presenting symptomatology impedes the development and implementation of effective treatments for traumatic brain injury (TBI). Objective tests that characterize the essential features of neural damage in blast-related brain injury are therefore required to advance clinical care. To date, very few studies have specificall investigated neural injury from blast. In a pilot investigation of Operation Iraqi Freedom and Operation Enduring Freedom (OIF/OEF) troops we found individuals with blast-related TBI (bTBI) exhibited diminished electroencephalography (EEG) phase synchronization between lateral frontal scalp sites of the two cerebral hemispheres (Sponheim et al., Neuroimage, 2011). Diminished synchrony was not accounted for by post-deployment psychopathology and was associated with the structural integrity of white matter tracts in the frontal lobes of bTBI subjecs. We are also near completion of a Department of Defense funded study investigating the use of EEG and Diffusion Tensor Imaging (DTI) measures to assess the functional and structural neural consequences of bTBI in a National Guard OIF/OEF sample. To date we have studied over 150 individuals divided into bTBI, bTBI+PTSD, PTSD, and control groups and found evidence of diffuse white matter abnormalities associated with bTBI. The question that the current proposal addresses is whether measures of neural structure (e.g., DTI) and function (EEG) have clinical utility in differentiating the effects of bTBI from post-traumatic psychopathology in veterans referred to a Regional VA Polytrauma Center. Hence, the goal of the proposed project is to validate measures of neural function and structure as means of separating the effects of bTBI from post-traumatic psychopathology in veterans being seen at a VA Polytrauma Center for evaluation. Specific Aim 1. We will determine whether EEG and DTI indices differentiate between bTBI and post- traumatic psychopathology in veterans who have screened positive for TBI and were referred to a Regional VA Polytrauma Center. Analyses will include testing for differential effects of bTBI and impact TBI (iTBI) on neural indices. We hypothesize that compared to individuals with only post-traumatic psychopathology, individuals with a bTBI will exhibit diminished EEG phase synchronization between brain regions and a greater percentage of white matter voxels with low fractional anisotropy (FA) as measured by DTI. Specific Aim 2. Given variability in the outcome of individuals affected by mild TBI (either blast or impact) we will determine how chronic EEG and white matter abnormalities predict long-term functioning in veterans who screened positive for TBI and were referred to a Regional VA Polytrauma Center. We hypothesize that greater abnormalities on EEG and DTI indices will be associated with functional impairment in subjects with mild TBI. Specific Aim 3. Because the adaptation of the brain to damage varies across individuals, we will carry out analyses to determine whether risk genes for neural injury mediate the association between the number and type (blast, impact) of TBI with the presence of chronic EEG and DTI abnormalities. We hypothesize that the ApoE 4 allele will be associated with greater abnormalities on neural indices in individuals who have sustained a mild TBI. PUBLIC HEALTH RELEVANCE: Brain injury from explosive blast is increasingly common in OIF/OEF cohorts of veterans. The Veterans Health Administration (VHA) has implemented a mandatory screening for traumatic brain injury (TBI) in order to document and treat veterans who are impaired by such an injury. Although the screening is helpful it results in many individuals with post-traumatic psychopathology being considered for a TBI given the overlap in the clinical presentations of the two conditions. The proposed project will improve the separation of mild TBI from post-traumatic psychopathology by describing the essential features of mild TBI in terms of enduring effects on neural function and structure. The study will provide an alternative method for parsing mild TBI from post- traumatic psychopathology that may serve as a guide for prescribing maximally effective interventions. Identification of essential neural features may also improve the definitio of mild TBI by increasing the objectivity of diagnosis through the use of neuroimaging laboratory tests.